HIV is known to primarily replicate in activated CD4+ T cells. In vitro studies have assessed the ability of HIV to replicate in multiple subsets of CD4+ T cells, and have identified several potential sources of T cells that are subject to infection by HIV. However, it remains unclear which CD4+ T cells are most frequently infected in vivo, and the impact of infection of these various subsets. This study seeks to define the subsets of CD4+ T cells that are naturally infected in patients, the anatomical sites of those infected cells and the impact upon HIV- and pathogen-specific immunity and the latent reservoir of HIV.